Dual D₂ and 5-HT_1A receptors binding affinities of 1-aryl-4-(diarylmethylene)piperazines and piperidines

Although atypical antipsychotics provide significantly greater efficacy against negative symptoms and cognitive deficits of schizophrenia, improvements in negative symptoms and cognition remain modest. The third generation antipsychotics which combine D₂ receptor blockade with 5-HT_1A receptor activation appear to provide therapeutic benefits against a broader range of symptoms and are essentially free of EPS liability. In an ongoing effort, we have identified new dihydroquinoline, tetrahydroquinoline and methoxyquinoline derivatives of 1-aryl-4-(diarylmethylene)piperazines and 4-aryl-1-diarylmethylene)piperidines, which are structural analogs of adoprazine (SLV313). The described compounds have been screened for binding affinities of D₂ and 5-HT_1A receptors. The structure-activity relationship studies indicated that cyclopentenylpyridine, fluorophenylpyridine and cyclopentenylbenzyl groups significantly contribute to the high-binding affinities of these compounds to D₂ and 5-HT_1A receptors.